The indenoisoquinolines are a class of cytotoxic molecules that have been demonstrated to inhibit topoisomerase I (top1) by intercalating between DNA bases at the enzyme's cleavage site. This mechanism of action is similar to the natural product camptothecin (1) and its clinically useful derivative topotecan (2) (see Kohlhagen G, et al., Mol. Pharmacol. 1998, 54, 50, incorporated herein by reference).

Thus, the indenoisoquinolines constitute a novel class of non-camptothecin top1 inhibitors. Mechanistically, the intercalation of these molecules elongates the DNA such that top1 cannot catalyze the religation of the DNA backbone (Staker B, et al., Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 15387). These inhibitors are therefore classified as top1 “poisons” as opposed to top1 “suppressors”, the latter of which inhibit the DNA cleavage reaction.
Indenoisoquinolines have been synthesized using methylenedioxy and di(methoxy) substituents as well as molecules that lack substituents on both the isoquinoline and indenone rings. Past synthetic efforts have focused on exploring the substitution pattern of the lactam nitrogen with a wide variety of carbon and heteroatom substituents. These efforts have resulted in the ability to potentiate the cytotoxicity and top1 inhibition of the indenoisoquinolines through the prudent selection of functionalities protruding from the lactam nitrogen.